Biochemistry and Molecular Biophysics
Publications (PubMed / NIH)
Research
The Janetka research laboratory is broadly interested in the X-ray structure-based drug design, medicinal chemistry and organic synthesis of chemical tools and small molecule drugs. In multiple drug discovery projects, we are developing inhibitors of proteases, kinases, lectins, and other protein targets for studying and treating cancer and a variety of infectious disease. One project is targeting several serine proteases including HGFA and hepsin which activate growth factors and cytokines in tumors. Another project is working on inhibitors of transmembrane serine proteases such as TMPRSS2 and matriptase as broad-spectrum antiviral drugs. We have a project focused on aspartic protease inhibitors and GPCR antagonists as novel therapy for River Blindness, caused by parasitic filarial worm infections. We are also working on phosphodiesterase inhibitors as well as inhibitors of PIM kinase and others as new anthelmintic drugs to treat intestinal worm infections caused by whipworm and hookworm. Further studies are directed on the rational design of CDPK1 kinase inhibitors as novel drugs to treat acute and cure chronic Toxoplasmosis. Finally, a large research effort is dedicated to the structure-guided design of glycomimetic lectin antagonists such as PapG as innovative antivirulence therapeutics for the treatment and prevention of bacterial infections and in one project targeting Fap2 for colon cancer.
Select Patents
Compounds and methods for treating bacterial infections (US Patent # 20180194792)
Inhibitors of growth factor activation enzymes (US Patent # 20180066015)
Select Books
Extracellular Targeting of Cell Signaling in Cancer: Strategies Directed at MET and RON Receptor Tyrosine Kinase Pathways, available from the publisher (Wiley), Amazon, Barnes & Noble, and other bookstores.
Select Publications
Liana Beld, Hyeim Jung, Christina A. Bulman, Bruce A. Rosa, Peter U. Fischer, James W. Janetka, Sara Lustigman, Judy A. Sakanari, and Makedonka Mitreva (2022). “Aspartyl Protease Inhibitors as Anti-Filarial Drugs” Pathogens. 2022 Jun 18;11(6):707. doi: 10.3390/pathogens11060707. (Abstract)
Vishnu C. Damalanka, Jorine J. L. P. Voss, Matthew W. Mahoney, Tina Primeau, Shunqiang Li, Lidija Klampfer, & James W. Janetka (2021). “Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression” J Med Chem. 2021 Dec 13. doi: 10.1021/acs.jmedchem.1c01671. Online ahead of print. (Abstract)
Matthew Mahoney, Vishnu C. Damalanka, Michael A. Tartell, Dong Hee Chung, André Luiz Lourenco, Dustin Pwee, Anne E. Mayer Bridwell, Markus Hoffmann, Jorine Voss, Partha Karmakar, Nurit Azouz, Andrea M. Klingler, Paul W. Rothlauf, Cassandra E. Thompson, Melody Lee, Lidija Klampfer, Christina Stallings, Marc E. Rothenberg, Stefan Pöhlmann, Sean P. Whelan, Anthony J. O’Donoghue, Charles S. Craik, & James W. Janetka (2021). “A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells” Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):e2108728118. doi: 10.1073/pnas.2108728118. (Abstract)
Lisa K. McLellan, Michael R. McAllaster, Arthur S. Kim, Ľubomíra Tóthová, Patrick D. Olson, Jerome S. Pinkner, Allyssa L. Daugherty, Teri N. Hreha, James W. Janetka, Daved H. Fremont, Scott J. Hultgren, Herbert W. Virgin, & David A Hunstad (2021). “A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis” PLoS Pathog. 2021 Jan 29;17(1):e1009314. doi: 10.1371/journal.ppat.1009314. eCollection 2021 Jan. (Abstract)
Rahul Tyagi, Christina A. Bulman, Fidelis Cho-Ngwa, Chelsea Fischer, Chris Marcellino, Michelle R. Arkin, James H. McKerrow, Case W. McNamara, Matthew Mahoney, Nancy Tricoche, Shabnam Jawahar, James W. Janetka, Sara Lustigman, Judy Sakanari, & Makedonka Mitreva (2021). “An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease” Pathogens. 2021 Jan 14;10(1):71. doi: 10.3390/pathogens10010071. (Abstract)
Vishnu C. Damalanka, Amarendar Reddy Maddirala, & James W. Janetka (2020). “Novel approaches to glycomimetic design: Development of small molecular weight lectin antagonists” Expert Opin Drug Discov. 2020 Dec 18. doi: 10.1080/17460441.2021.1857721. Online ahead of print. (Abstract)
James W Janetka, Allen T Hopper, Ziping Yang, Jennifer Barks, Mary Savari Dhason, Qiuling Wang, & L David Sibley (2020). “Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis” J Med Chem. 2020 Jun 11;63(11):6144-6163. doi: 10.1021/acs.jmedchem.0c00419. Epub 2020 Jun 1. (Abstract)
Yang B., Hird A.W., Bodnarchuk M.S., Zheng X., Dakin L., Su Q., Daly K., Godin R., Hattersley M.M., Brassil P., Redmond S., John Russell D., & Janetka J.W. (2020). “Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254).” Bioorg Med Chem. 2020 Jan 15;28(2):115227. doi: 10.1016/j.bmc.2019.115227. Epub 2019 Dec 11. (Abstract)
Vishnu C. Damalanka, Scott A. Wildman, & James W. Janetka (2019). “Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin” MedChemComm. 18 Jul 2019, doi: 10.1039/C9MD00234K (Abstract)
Tyagi R., Elfawal M.A., Wildman S.A., Helander J., Bulman C.A., Sakanari J., Rosa B.A., Brindley P.J., Janetka J.W., Aroian R.V., & Mitreva M. (2019). “Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics.” Sci Rep. 2019 Jun 24;9(1):9085. doi: 10.1038/s41598-019-45548-7. (Abstract)
Damalanka V.C. & Janetka J.W. (2019). “Recent progress on inhibitors of the type II transmembrane serine proteases, hepsin, matriptase and matriptase-2.” Future Med Chem. 2019 Apr;11(7):743-769. doi: 10.4155/fmc-2018-0446. Epub 2019 Apr 4. (Abstract)
Maddirala A., Klein R.D., Pinkner J., Kalas V., Hultgren S.J., & Janetka J.W. (2019). “Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through iterative rational drug design.” J Med Chem. 2019 Jan 24;62(2):467-479. doi: 10.1021/acs.jmedchem.8b01561. Epub 2019 Jan 2. (Abstract)
Damalanka V.C., Han Z., Karmakar P., O’Donoghue A.J., La Greca F., Kim T., Pant S., Helander J., Klefström J., Craik C.S., & Janetka J.W. (2019). “Discovery of Selective Matriptase and Hepsin Serine Protease Inhibitors: Useful Chemical Tools for Cancer Cell Biology.” J Med Chem. 2019 Jan 24;62(2):480-490. doi: 10.1021/acs.jmedchem.8b01536. Epub 2019 Jan 4. (Abstract)
Kawaguchi M., Yamamoto K., Takeda N., Fukushima T., Yamashita F., Sato K., Kitamura K., Hippo Y., Janetka J.W., & Kataoka H. (2019). “Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine.” Commun Biol. 2019 Jan 4;2:11. doi: 10.1038/s42003-018-0255-8. eCollection 2019. (Abstract)
Tyagi R., Maddirala A.R., Elfawal M., Fischer C., Bulman C.A., Rosa B.A., Gao X., Chugani R., Zhou M., Helander J., Brindley P.J., Tseng C.C., Greig I.R., Sakanari J., Wildman S.A., Aroian R., Janetka J.W., & Mitreva M. (2018). “Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics.” ACS Infect Dis. 2018 Jul 13;4(7):1130-1145. doi: 10.1021/acsinfecdis.8b00090. Epub 2018 May 14. (Abstract)